Anti-aging Pathway Questioned

A new study raises further doubts about the ability of proteins called sirtuins to slow aging, but the controversy remains unsettled.

By Tia Ghose | September 21, 2011

An elderly manFLICKR, BLEU MAN

A new study adds fuel to the fire against the notion that a class of proteins called sirtuins can prolong life. The proteins generated significant excitement when earlier studies showed they could increase lifespan in several animal species, but several groups’ inability to repeat the results raised doubts about the finding. The new study, published today (September 21) in Nature, provides the most convincing evidence yet against sirtuins’ role in aging.

“It’s an important paper,” said Brian Kennedy, an aging researcher and President of the Buck Institute for Research on Aging, but it is unlikely to lay the controversy to rest. “The thing we still have to understand—from yeast all the way to mice—is whether enhanced sirtuin activity expands lifespan,” said Kennedy, who was not involved in the study. “That’s really an open question right now.”

Anti-aging pill?

For decades, researchers have found that cutting calories can extend lifespan in species from worms to rhesus monkeys. “So one of the long-term dreams of aging was that you could have a pill that would mimic the effects of dietary restriction because it could slow human aging,” said study co-author David Gems, a biogerontologist at the University College London.

In 1995, a potential drug target emerged. When Kennedy, MIT molecular biologist Leonard Guarente, and colleagues targeted a gene which silenced sirtuins, a class of proteins that plays a role in several metabolic pathways, they increased the number of times yeast cells divide by 30 percent. In 2001, Guarente and his colleagues showed that transgenic worms that over-express a specific sirtuin called sir2 lived longer, and others showed that dietary restriction increased life span in fruit flies by way of a sirtuin pathway.

Taken together, the studies created a compelling story: cutting calories activates a sirtuin pathway, which extends lifespan in many animal species. That raised hopes that scientists could one day create a human anti-aging pill by stimulating sirtuin production directly, bypassing the need to skimp on calories. A company called Sirtris Pharmaceuticals even formed to develop anti-aging compounds that could do just that.

Doubts emerge

While some labs saw dramatic life extension with sirtuins, other groups had trouble replicating those findings. After three years without success, Gems and his colleagues began to suspect the genetic background was confounding their studies. In other words, the method for activating the sir2 gene in worms and fruit flies may have inadvertently introduced other genetic mutations that increasing longevity.

To weed out this genetic background, he and his colleagues created transgenic worms that overexpressed sir2 using the same method for gene insertion that Guarente originally used in his long-lived worms. The researchers mated the transgenic worms with wild-type animals and selected for offspring that still expressed high levels of sir2. Those worms were mated again with wild-type worms. After six generations, the resultant worms still made more sir2, but were genetically almost identical to wild type.

C. elegans

WIKIMEDIA COMMONS, NATIONAL HUMAN GENOME RESEARCH INSTITUTE

The outcrossed sir2 worms did not live longer than the wild-type controls, suggesting that some other gene must account for life extension in the original worms. Sure enough, a little more digging revealed another mutation in a neurodegeneration pathway that was responsible for the longevity effect. When they took a second look at flies, they found the same story: sirtuins didn’t seem to extend lifespan compared to genetically similar controls.

To see whether dietary restriction’s increased longevity depends on the sirtuin pathway, the group knocked out sir2 expression in flies and put them on a meager diet. The flies still lived longer, suggesting that sirtuins were not responsible.

Gems thinks the new findings should lay to rest the notion that sirtuins play a major role in extending lifespan across species. “Because of what a huge paradigm sirtuins created, it’s quite extraordinary that it’s sort of vanishing so suddenly,” he said. “It’s like a bubble popping.”

Continued Controversy

But not everyone in the anti-aging community is ready to abandon sirtuins. In a Brief Communications Arising published in the same issue of Nature, Guarente, who published the first studies showing dramatic life extension in worms, said they also later recognized the problem with their transgenic method. However, when they corrected for it in further experiments, they found a smaller, but still significant, 10 to 14 percent increase in lifespan in worms. The effect has since been confirmed by another lab in a study published this year in PLoS Genetics, he said.

“I do not agree with the notion that in worms, sirtuins do not regulate aging. I think that’s wrong,” Guarente said.

Stephen Helfand, a molecular biologist at Brown University who did some of the original work showing life extension in fruit flies, also took issue with the conclusions of the Gems paper. In 2009, his group confirmed that sirtuins extended life in fruit flies, using a careful method that eliminates the problem of genetic background, he said. He also faults the current paper for not replicating all the conditions used in his original experiments.

But the modest effect found in the more recent studies isn’t particularly exciting, Kennedy said. “In Lenny’s paper the effects are 10 to 14 percent,” but hundreds of genes in worms can extend lifespan by that much, he added.

Furthermore, the findings in flies and worms may not be central to the question of sirtuins and aging, Kennedy said. “Really what we care about is humans, and the best way to understand that is to have better data in mice.”

While the jury is still out on sirtuins and longevity in mammals, there’s no question that they extend health. “There’s a huge body of work that implicates sirtuins in suppression of many age-related disorders in mammals,” such as cardiac fibrosis, diabetes, obesity, neurodegeneration, and even age-related hearing loss, said David Lombard, a biogerontologist at the University of Michigan, Ann Arbor, who wrote an accompanying News and Views piece in Nature.

And while the debate over sirtuins’ role in aging rages on, biologists will continue to investigate other potential targets, such as the Target of Rapamycin (TOR) pathway. “It’s been shown that other pathways have very dramatic effects on aging which are not controversial and have not been challenged,” Gems said. “There’s lots of activity elsewhere in the field moving towards drug treatments for aging.”

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Anonymous

September 22, 2011

Aging involves many genes, not one.Â Recently one group of researchers identified 295 human genes activated among long-living humans.Â To develop an anti-aging pill it would likely need to address a broad range of genes.Â Even single-gene targeted drugs have not been effective in treating disease.Â The advantage of small molecules like red wine resveratrol is that it influences hundreds of genes, and therefore is a potential candidate for an anti-aging pill.Â

A DR.Frank from New york was using and treating patients' with high doses of purines andÂ Rna,Â Â he was reversing effects of aging and disease processes.Â I think more concentration needs to be placed on what the body needs to live longer and repair itself, rather than turning off genes that can effect the whole genome...

Â A common but serious error is using animalmodels that are genetically identical or similar - when an interventionincreases lifespan, it often is just benefiting the specific causes of death inthat individual rather than retarding aging. Â Models such as 4 straincrosses, or even better, the Diversity Outbred mice of Gary Churchill, avoidthis problem. Â A useful cross is illustrated in studies by the NIAintervention program (Nature 460:392-5, 2009; Â J Gerontol A Biol Sci Med Sci. 66(2):191-201; 2011).Â The latter study found no increase inlifespan from resveratrol at the two doses recommended by David Sinclair, aco-author.Â However this does notconflict with findings that B6 male mice fed very high fat which get type IIdiabetes benefit from resveratrol, which may protect from type II diabetes, atleast in that mouse strain. Â Thus there is not as much contradiction as this article indicates. Â I have seen no contradictions to the fact that resveratrol does not increase lifespans in healthy mouse genotypes fed normal low fat mouse diets.Â

How much science want to prolongÂ lifespan? From ancient people are trying to prolongÂ lifespan but all are unsuccessful Ayurveda Indian medical system .expected 100 years man can live.BibleÂ told 70 is limit.Recent development in scienceÂ increased the life span of mankind, we are experiences population explosion world over .and suffering drawback of over population.Extreme old age is curse to family,society and nation.It is burden to mankind.I request to scientist please obey the law of nature.and stop this increasing lifespan.Man must live till he is fit for physical and mentalÂ work.beyond that living is suffering many diseases and live life on depend on others.

It's still not clear just what aging is, if a disease, or just bodily machinery becoming rusty and not working smoothly. Â Can some "lubricant" such as resveratrol promote good health, even into advanced age. The degenerative diseases of again, Alzheimer, Parkinsons, probably ALS, atherosclerosis, and the frailty of age are the real problem. Â If they can be retarded so people can live useful, productive lives into later years, then aging will not be a curse. Telomerase seems to be a target for longevity, although difficult to target on a practical basis.Â Â Another concern is dysfunctional proteins, again the rusty hypothesis, but proteins such as insulin and ceruloplasmin, or biologically functional proteins may through accumulating miss-translation during again, probably become dysfunctional the aged, resulting in altered function and accumulation of minerals and compounds which would become poisons when present in abnormal quantities, such as copper in Alzheimer disease, and iron in Parkinsons.Â Â Â Also as digestion and the bowel wall breaks down (leaky bowel syndrome) during aging, abnormal amino acids and partially digested protein fragments probably are absorbed into the body and may act as poisons on normal functions, and displacing critical amino-acids necessary for normal metabolism resulting in tissue starvation.Â Â Â There are a lot of targets and organ systems to stabilize during aging, to reduce the destructiveness of aging. Probably it is analgous to Â a war with an invading enemy, with many different elements, infantry, artillery, armor, air, all of which have their effects and must be met in their particular fashion. In any war, there are inevitable losses, but with a coordinated effort the war might still be won.Â

Well since it is already known that diet and exercise increase lifespan, why don't we just eat less and exercise more? :) We will not only live longer but also healthier. I would add taking care of the internal microbiom, diet with antioxidants and not overloaded with sugar and meat. And the society will not need to spend milions on finding "a pill" that will extend the lifespan but perhaps leave us, as rameshraghuvanshi suggested, burden to the society.

Aging involves many genes, not one.Â Recently one group of researchers identified 295 human genes activated among long-living humans.Â To develop an anti-aging pill it would likely need to address a broad range of genes.Â Even single-gene targeted drugs have not been effective in treating disease.Â The advantage of small molecules like red wine resveratrol is that it influences hundreds of genes, and therefore is a potential candidate for an anti-aging pill.Â

A DR.Frank from New york was using and treating patients' with high doses of purines andÂ Rna,Â Â he was reversing effects of aging and disease processes.Â I think more concentration needs to be placed on what the body needs to live longer and repair itself, rather than turning off genes that can effect the whole genome...

Â A common but serious error is using animalmodels that are genetically identical or similar - when an interventionincreases lifespan, it often is just benefiting the specific causes of death inthat individual rather than retarding aging. Â Models such as 4 straincrosses, or even better, the Diversity Outbred mice of Gary Churchill, avoidthis problem. Â A useful cross is illustrated in studies by the NIAintervention program (Nature 460:392-5, 2009; Â J Gerontol A Biol Sci Med Sci. 66(2):191-201; 2011).Â The latter study found no increase inlifespan from resveratrol at the two doses recommended by David Sinclair, aco-author.Â However this does notconflict with findings that B6 male mice fed very high fat which get type IIdiabetes benefit from resveratrol, which may protect from type II diabetes, atleast in that mouse strain. Â Thus there is not as much contradiction as this article indicates. Â I have seen no contradictions to the fact that resveratrol does not increase lifespans in healthy mouse genotypes fed normal low fat mouse diets.Â

How much science want to prolongÂ lifespan? From ancient people are trying to prolongÂ lifespan but all are unsuccessful Ayurveda Indian medical system .expected 100 years man can live.BibleÂ told 70 is limit.Recent development in scienceÂ increased the life span of mankind, we are experiences population explosion world over .and suffering drawback of over population.Extreme old age is curse to family,society and nation.It is burden to mankind.I request to scientist please obey the law of nature.and stop this increasing lifespan.Man must live till he is fit for physical and mentalÂ work.beyond that living is suffering many diseases and live life on depend on others.

It's still not clear just what aging is, if a disease, or just bodily machinery becoming rusty and not working smoothly. Â Can some "lubricant" such as resveratrol promote good health, even into advanced age. The degenerative diseases of again, Alzheimer, Parkinsons, probably ALS, atherosclerosis, and the frailty of age are the real problem. Â If they can be retarded so people can live useful, productive lives into later years, then aging will not be a curse. Telomerase seems to be a target for longevity, although difficult to target on a practical basis.Â Â Another concern is dysfunctional proteins, again the rusty hypothesis, but proteins such as insulin and ceruloplasmin, or biologically functional proteins may through accumulating miss-translation during again, probably become dysfunctional the aged, resulting in altered function and accumulation of minerals and compounds which would become poisons when present in abnormal quantities, such as copper in Alzheimer disease, and iron in Parkinsons.Â Â Â Also as digestion and the bowel wall breaks down (leaky bowel syndrome) during aging, abnormal amino acids and partially digested protein fragments probably are absorbed into the body and may act as poisons on normal functions, and displacing critical amino-acids necessary for normal metabolism resulting in tissue starvation.Â Â Â There are a lot of targets and organ systems to stabilize during aging, to reduce the destructiveness of aging. Probably it is analgous to Â a war with an invading enemy, with many different elements, infantry, artillery, armor, air, all of which have their effects and must be met in their particular fashion. In any war, there are inevitable losses, but with a coordinated effort the war might still be won.Â

Well since it is already known that diet and exercise increase lifespan, why don't we just eat less and exercise more? :) We will not only live longer but also healthier. I would add taking care of the internal microbiom, diet with antioxidants and not overloaded with sugar and meat. And the society will not need to spend milions on finding "a pill" that will extend the lifespan but perhaps leave us, as rameshraghuvanshi suggested, burden to the society.

Aging involves many genes, not one.Â Recently one group of researchers identified 295 human genes activated among long-living humans.Â To develop an anti-aging pill it would likely need to address a broad range of genes.Â Even single-gene targeted drugs have not been effective in treating disease.Â The advantage of small molecules like red wine resveratrol is that it influences hundreds of genes, and therefore is a potential candidate for an anti-aging pill.Â

A DR.Frank from New york was using and treating patients' with high doses of purines andÂ Rna,Â Â he was reversing effects of aging and disease processes.Â I think more concentration needs to be placed on what the body needs to live longer and repair itself, rather than turning off genes that can effect the whole genome...

Â A common but serious error is using animalmodels that are genetically identical or similar - when an interventionincreases lifespan, it often is just benefiting the specific causes of death inthat individual rather than retarding aging. Â Models such as 4 straincrosses, or even better, the Diversity Outbred mice of Gary Churchill, avoidthis problem. Â A useful cross is illustrated in studies by the NIAintervention program (Nature 460:392-5, 2009; Â J Gerontol A Biol Sci Med Sci. 66(2):191-201; 2011).Â The latter study found no increase inlifespan from resveratrol at the two doses recommended by David Sinclair, aco-author.Â However this does notconflict with findings that B6 male mice fed very high fat which get type IIdiabetes benefit from resveratrol, which may protect from type II diabetes, atleast in that mouse strain. Â Thus there is not as much contradiction as this article indicates. Â I have seen no contradictions to the fact that resveratrol does not increase lifespans in healthy mouse genotypes fed normal low fat mouse diets.Â

How much science want to prolongÂ lifespan? From ancient people are trying to prolongÂ lifespan but all are unsuccessful Ayurveda Indian medical system .expected 100 years man can live.BibleÂ told 70 is limit.Recent development in scienceÂ increased the life span of mankind, we are experiences population explosion world over .and suffering drawback of over population.Extreme old age is curse to family,society and nation.It is burden to mankind.I request to scientist please obey the law of nature.and stop this increasing lifespan.Man must live till he is fit for physical and mentalÂ work.beyond that living is suffering many diseases and live life on depend on others.

It's still not clear just what aging is, if a disease, or just bodily machinery becoming rusty and not working smoothly. Â Can some "lubricant" such as resveratrol promote good health, even into advanced age. The degenerative diseases of again, Alzheimer, Parkinsons, probably ALS, atherosclerosis, and the frailty of age are the real problem. Â If they can be retarded so people can live useful, productive lives into later years, then aging will not be a curse. Telomerase seems to be a target for longevity, although difficult to target on a practical basis.Â Â Another concern is dysfunctional proteins, again the rusty hypothesis, but proteins such as insulin and ceruloplasmin, or biologically functional proteins may through accumulating miss-translation during again, probably become dysfunctional the aged, resulting in altered function and accumulation of minerals and compounds which would become poisons when present in abnormal quantities, such as copper in Alzheimer disease, and iron in Parkinsons.Â Â Â Also as digestion and the bowel wall breaks down (leaky bowel syndrome) during aging, abnormal amino acids and partially digested protein fragments probably are absorbed into the body and may act as poisons on normal functions, and displacing critical amino-acids necessary for normal metabolism resulting in tissue starvation.Â Â Â There are a lot of targets and organ systems to stabilize during aging, to reduce the destructiveness of aging. Probably it is analgous to Â a war with an invading enemy, with many different elements, infantry, artillery, armor, air, all of which have their effects and must be met in their particular fashion. In any war, there are inevitable losses, but with a coordinated effort the war might still be won.Â

Well since it is already known that diet and exercise increase lifespan, why don't we just eat less and exercise more? :) We will not only live longer but also healthier. I would add taking care of the internal microbiom, diet with antioxidants and not overloaded with sugar and meat. And the society will not need to spend milions on finding "a pill" that will extend the lifespan but perhaps leave us, as rameshraghuvanshi suggested, burden to the society.

It is common for people to present diverse opinions. More so for the question of aging and longevity. People go to disregard logic as well as the progress science has made in this field. They will often confuse living longer with weakness and disability. Which is just not so.I would like the readers to go through a chapter from my book, "Ageing slowly, Living longer".

I think we people now try to finding the thing which we are on the way ofÂ losingÂ but we finding it on wrong way.In India still there are some people who crossed 100 years of there life. These peoples never eat any anti aging pill & never take any research institute treatment. The reason for their long life is they follow nature's rule. We need to teach how they follow it & how they do it. Answer for anti ageing itÂ aroundÂ us the need is to just find it in correct way no need to do huge research in lab. Â Â

It is common for people to present diverse opinions. More so for the question of aging and longevity. People go to disregard logic as well as the progress science has made in this field. They will often confuse living longer with weakness and disability. Which is just not so.I would like the readers to go through a chapter from my book, "Ageing slowly, Living longer".

I think we people now try to finding the thing which we are on the way ofÂ losingÂ but we finding it on wrong way.In India still there are some people who crossed 100 years of there life. These peoples never eat any anti aging pill & never take any research institute treatment. The reason for their long life is they follow nature's rule. We need to teach how they follow it & how they do it. Answer for anti ageing itÂ aroundÂ us the need is to just find it in correct way no need to do huge research in lab. Â Â

It is common for people to present diverse opinions. More so for the question of aging and longevity. People go to disregard logic as well as the progress science has made in this field. They will often confuse living longer with weakness and disability. Which is just not so.I would like the readers to go through a chapter from my book, "Ageing slowly, Living longer".

I think we people now try to finding the thing which we are on the way ofÂ losingÂ but we finding it on wrong way.In India still there are some people who crossed 100 years of there life. These peoples never eat any anti aging pill & never take any research institute treatment. The reason for their long life is they follow nature's rule. We need to teach how they follow it & how they do it. Answer for anti ageing itÂ aroundÂ us the need is to just find it in correct way no need to do huge research in lab. Â Â

Aging Is Also An E/m Matter,Like each and all things in the universe.Â Â A.There is neither alchemy nor mystery in aging. Aging is an E/m, energy/mass,Â matter. Â The universe is a two-poles affair. It evolves cyclically between two poles: an all-mass Big-Bang pole and a nearly-all-energy pole. Presently all the singularity mass is reconverting to energy, to energy that drives apart the galaxies clusters. In the energy-mass dualism mass thus diminishes as energy increases andÂ the speed ofÂ separating clusters is, in accordance with Newton,Â accelerating.Â Since thus every mass format, the totality of its components, are destined to reconvert to energy, the format must continuously take in energy or massÂ to postpone its own reconversion events.Â The in-takers of energy range from the biggest black hole to the electric neutrino, including living organisms. This is whatÂ â€œnatural selectionâ€쳌 is all about. Natural selection is about ALL the E/m reconversions in the universe. Â B.See â€œ Aging Seen Without The Emperorâ€™s New Clothesâ€쳌March 9, 2009 http://ouroboros.wordpress.com...Â C. Slowing aging is postponing of mass reconversion(s) event(s) of organisms, genes/genomes, and/or of the other systemâ€™s components.Â Â About time that â€œscientistsâ€쳌 refresh conceptions and comprehensions and attitudes and research plans and peer-reviewings. Let their science evolveâ€¦Â Dov Henis(comments from 22nd century)http://universe-life.com/

Aging Is Also An E/m Matter,Like each and all things in the universe.Â Â A.There is neither alchemy nor mystery in aging. Aging is an E/m, energy/mass,Â matter. Â The universe is a two-poles affair. It evolves cyclically between two poles: an all-mass Big-Bang pole and a nearly-all-energy pole. Presently all the singularity mass is reconverting to energy, to energy that drives apart the galaxies clusters. In the energy-mass dualism mass thus diminishes as energy increases andÂ the speed ofÂ separating clusters is, in accordance with Newton,Â accelerating.Â Since thus every mass format, the totality of its components, are destined to reconvert to energy, the format must continuously take in energy or massÂ to postpone its own reconversion events.Â The in-takers of energy range from the biggest black hole to the electric neutrino, including living organisms. This is whatÂ â€œnatural selectionâ€쳌 is all about. Natural selection is about ALL the E/m reconversions in the universe. Â B.See â€œ Aging Seen Without The Emperorâ€™s New Clothesâ€쳌March 9, 2009 http://ouroboros.wordpress.com...Â C. Slowing aging is postponing of mass reconversion(s) event(s) of organisms, genes/genomes, and/or of the other systemâ€™s components.Â Â About time that â€œscientistsâ€쳌 refresh conceptions and comprehensions and attitudes and research plans and peer-reviewings. Let their science evolveâ€¦Â Dov Henis(comments from 22nd century)http://universe-life.com/

Aging Is Also An E/m Matter,Like each and all things in the universe.Â Â A.There is neither alchemy nor mystery in aging. Aging is an E/m, energy/mass,Â matter. Â The universe is a two-poles affair. It evolves cyclically between two poles: an all-mass Big-Bang pole and a nearly-all-energy pole. Presently all the singularity mass is reconverting to energy, to energy that drives apart the galaxies clusters. In the energy-mass dualism mass thus diminishes as energy increases andÂ the speed ofÂ separating clusters is, in accordance with Newton,Â accelerating.Â Since thus every mass format, the totality of its components, are destined to reconvert to energy, the format must continuously take in energy or massÂ to postpone its own reconversion events.Â The in-takers of energy range from the biggest black hole to the electric neutrino, including living organisms. This is whatÂ â€œnatural selectionâ€쳌 is all about. Natural selection is about ALL the E/m reconversions in the universe. Â B.See â€œ Aging Seen Without The Emperorâ€™s New Clothesâ€쳌March 9, 2009 http://ouroboros.wordpress.com...Â C. Slowing aging is postponing of mass reconversion(s) event(s) of organisms, genes/genomes, and/or of the other systemâ€™s components.Â Â About time that â€œscientistsâ€쳌 refresh conceptions and comprehensions and attitudes and research plans and peer-reviewings. Let their science evolveâ€¦Â Dov Henis(comments from 22nd century)http://universe-life.com/